Macrocyclic Ring Size Research Articles

Impact of ring size on the C[sbnd]H activation reactivity of iron(IV)–oxo complexes: A computational study with TMC macrocycles

Here, a DFT investigation has been presented to demonstrate the relevance of the macrocyclic ligand ring size of the high-valent Fe(IV)O complex-catalyzed CH activation process. A nonheme iron-oxo compound bound with extensively studied macrocycle tetramethylcyclam (TMC) with varying ring size measures in terms of n = 12, 13, 14, 15, and 16 in [Fe(IV)O(n-TMC)(CH3CN)]2+ has been considered as the oxidant and dihydroanthracene as the general substrate. Counterions, as always, have been considered to avoid the self-interaction error in these DFT calculations. Computations were carried out to determine the effect of the axial ligand, acetonitrile, on the CH activation reactivity. It has been discovered that the complexes without axial ligands turned out to be more reactive compared to their axially coordinated counterparts. The most intriguing finding, however, has been that reactivity increased steadily with ring size increments, giving us the trend 12 < 13 < 14 < 15 < 16. Behind this typical pattern of reactivity, several factors played a role, including the energy of the electron acceptor orbital, which sequentially decreases, and the distortion energy to achieve the transition state, which also decreases as we move on from n = 12 to 16. The triplet-quintet energy difference of the oxidants also has a part to play, as it decreases with increased ring size, with the quintet becoming more and more dominant. The current studies have also been able to corroborate the experimental data that was published regarding Fe(IV)O(13-TMC) (without axial syn form) having a higher CH activation reactivity than Fe(IV)O(14-TMC) (with axial anti form). On the whole, this computational exploration gives us a reactivity pattern based on the ring size commutes and can lead to successful experimental results if pursued based on this reaction.

Concise Total Syntheses of (+)‐Brefeldin A, Diastereomers and Analogs and Their Biological Activity

AbstractBrefeldin A is an important natural product and biochemical tool with cell‐modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)‐brefeldin A (BFA), 2‐epi‐BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five‐membered ring fragment was constructed by a short three‐step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross‐metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non‐natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times.

Structural Diversity in Divalent Group 14 Triflate Complexes Involving Endocyclic Thia-Macrocyclic Coordination.

A highly unusual series of M(II) (M = Ge, Sn, Pb) complexes with endocyclic thioether macrocyclic coordination and with coordination numbers ranging from three to nine have been prepared by the reaction of [9]aneS3 (1,4,7-trithiacyclononane), [12]aneS4 (1,4,7,10-tetrathiacyclododecane), or [24]aneS8 (1,4,7,10,13,16,19,22-octathiacyclotetracosane) with M(OTf)2 (M = Sn and Pb; OTf = CF3SO3-) or with GeCl2·dioxane and 2 mol equiv of TMSOTf (Me3SiO3SCF3) in a mixture of anhydrous CH2Cl2 and MeCN. The isolated bulk products are characterized by 1H, 13C{1H}, 19F{1H}, and 119Sn{1H} NMR and IR spectroscopy, high-resolution ESI+ MS, and microanalytical data. Crystal structures are also reported for [M(L)][OTf]2 (M = Ge, Sn, Pb; L = [9]aneS3, [12]aneS4) and for [M([24]aneS8)][OTf]2 (M = Sn, Pb). In all cases, the ligand is bound in an endocyclic fashion, but the coordination environment and number are highly dependent on the group 14 ion, the macrocyclic ring size, and the number of S-donor atoms it presents. Solution NMR spectroscopic data suggest that the metal-macrocycle coordination is retained in solution but that the triflate anions are extensively dissociated on the NMR timescale. Density functional theory calculations on the [M([9]aneS3)]2+ and [M([12]aneS4)]2+ (M = Ge, Sn, Pb) dications reveal that the HOMO is centered on the group 14 atom as a directional "lone pair"; it also retains a significant amount of positive charge.

Evaluation of the Effect of Macrocyclic Ring Size on [203Pb]Pb(II) Complex Stability in Pyridyl-Containing Chelators.

As an element-equivalent theranostic pair, lead-203 (203Pb, 100% EC, half-life = 51.92 h) and lead-212 (212Pb, 100% β-, half-life = 10.64 h), through the emission of γ rays and an α particle in its decay chain, respectively, can aid in the development of personalized targeted radionuclide treatment for advanced and currently untreatable cancers. With these isotopes currently being used in clinical trials, an understanding of the relationship between the chelator structure, ability to incorporate the radiometal, and metal-complex stability is needed to help design appropriate chelators for clinical use. Herein, we report an investigation into the effect of ring size in macrocyclic chelators where pyridine, an intermediate Lewis base, acts as an electron donor toward lead. Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), and NOON-2Py (7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) were synthesized and analyzed for their ability to coordinate Pb2+. Metal complex stability was investigated via [203Pb]Pb2+ radiolabeling studies, 1H NMR spectroscopy, X-ray crystallography, and potentiometry. With the smallest macrocyclic backbone, cyclen-4Py had the highest radiochemical yield, while, in descending order, crown-4Py and NOON-2Py had the lowest. Thermodynamic stability constants (log KML) of 19.95(3), 13.29(5), and 11.67 for [Pb(Cyclen-4Py)]2+, [Pb(Crown-4Py)]2+, and [Pb(NOON-2Py)]2+, respectively, correlated with their radiochemical yields. The X-ray crystal structure of the least stable complexes [Pb(NOON-2Py)]2+ revealed a hemidirected Pb2+ center, as reflected by a void within the coordination sphere, and [Pb(Crown-4Py)]2+ showed an average Pb-N pyridine interatomic distance of >3 Å. By contrast, the crystal structure of [Pb(Cyclen-4Py)]2+ showed shorter Pb-N pyridine interactions, and in solution, only one highly symmetric isomer existed for this complex, whereas conformational flexibility was observed for both [Pb(Crown-4Py)]2+ and [Pb(NOON-2Py)]2+ at the NMR timescale. This study illustrates the importance of the macrocyclic backbone size when incorporating bulky electron-donor groups into the design of a macrocyclic chelator as it affects the accessibility of lead to the donor arms. Our results show that cyclen-4Py is a promising chelator for future studies with this theranostic pair.

P-192 - Evaluation of the effect of macrocyclic ring size on Pb(II) and Cu(II) complex stability in pyridyl containing chelators

P-192 - Evaluation of the effect of macrocyclic ring size on Pb(II) and Cu(II) complex stability in pyridyl containing chelators

Pyridyldiimine macrocyclic ligands: Influences of template ion, linker length and imine substitution on ligand synthesis, structure and redox properties

A series of 2,6-diiminopyridine-derived macrocyclic ligands have been synthesized via [2 + 2] condensation around alkaline earth metal triflate salts. The inclusion of a tert-butyl group at the 4-position of the pyridine ring of the macrocyclic synthons results in macrocyclic complexes that are soluble in common organic solvents, thereby enabling a systematic comparison of the physical properties of the complexes by NMR spectroscopy, mass spectrometry, solution-phase UV–Vis spectroscopy, cyclic voltammetry and single-crystal X-ray crystallography. Solid-state structures determined crystallographically demonstrate increased twisting in the ligand, concurrent with either a decrease in ion size or an increase in macrocycle ring size (18, 20, or 22 membered rings). The degree of folding and twisting within the macrocycle can be quantified using parameters derived from the Npyr-M-Npyr bond angle and the relative orientation of the pyridinediimine (PDI) and pyridinedialdimine (PDAI) fragments to each other within the solid state structures. Cyclic voltammetry and UV–Vis spectroscopy were used to compare the relative energies of the imine π* orbital of the redox active PDI and PDAI components in the macrocycle when coordinated to redox inactive metals. Both methods indicate the change from a methyl to hydrogen substitution on the imine carbon lowers the energy of the ligand π* system.

Computer-Assisted Design of Macrocyclic Chelators for Actinium-225 Radiotherapeutics.

Actinium-225 (225Ac) is an excellent candidate for targeted radiotherapeutic applications for treating cancer, because of its 10-day half-life and emission of four high-energy α2+ particles. To harness and direct the energetic potential of actinium, strongly binding chelators that remain stable in vivo during biological targeting must be developed. Unfortunately, controlling chelation for actinium remains challenging. Actinium is the largest +3 cation on the periodic table and has a 6d05f0 electronic configuration, and its chemistry is relatively unexplored. Herein, we present theoretical work focused on improving the understanding of actinium bonding with macrocyclic chelating agents as a function of (1) macrocycle ring size, (2) the number and identity of metal binding functional groups, and (3) the length of the tether linking the metal binding functional group to the macrocyclic backbone. Actinium binding by these chelators is presented within the context of complexation with DOTA4-, the most relevant Ac3+ binding agent for contemporary radiopharmaceutical applications. The results enabled us to develop a new strategy for actinium chelator design. The approach is rooted in our identification that Ac3+-chelation chemistry is dominated by ionic bonding interactions and relies on (1) maximizing electrostatic interactions between the metal binding functional group and the Ac3+ cation and (2) minimizing electronic repulsion between negatively charged actinium binding functional groups. This insight will provide a foundation for future innovation in developing the next generation of multifunctional actinium chelators.

Rotaxanes comprising cyclic phenylenedioxydiacetamides and secondary mono- and bis-dialkylammonium ions: effect of macrocyclic ring size on pseudorotaxane formation

[2]Rotaxanes, stabilized through multiple and cooperative hydrogen bonding system, were synthesized from dialkylammonium ions and macrocycle possessing two phenylenedioxydiacetamide units and appropriate spacers.

Effect of ring rize on photoisomerization properties of stiff stilbene macrocycles.

A series of stiff stilbene macrocycles have been studied to investigate the possible impact of the macrocycle ring size on their photodynamic properties. The results show that reducing the ring size counteracts the photoisomerization ability of the macrocycles. However, even the smallest macrocycle studied (stiff stilbene subunits linked by a six carbon chain) showed some degree of isomerization when irradiated. DFT calculations of the energy differences between the E- and Z-isomers show the same trend as the experimental results. Interestingly the DFT study highlights that the energy difference between the E- and Z-isomers of even the largest macrocycle (linked by a twelve carbon chain) is significantly higher than that of the stiff stilbene unit itself. In general, it is indicated that addition of even a flexible chain to the stiff stilbene unit may significantly affect its photochemical properties and increase the photostability of the resulting macrocycle.

A study on the effect of the macrocycle ring size and R-group chain length on the optical properties of the CuPc thin films

Optical properties of spin-coated films of copper phthalocyanine (CuPc) are investigated by using UV–visible spectroscopy. The absorption spectra were recorded in the UV–visible region and showed two absorption bands of the phthalocyanine molecules, namely, the Soret (B) and the Q-band. The UV–visible spectrum is used to calculate the physical parameters of the thin film under investigation such as absorption A, reflectance R, refractive index n, extinction coefficient k, optical conductivity σopt and optical band gap Eg values. The obtained refractive index and the extinction coefficient values vary from 1.5 to 2.5 and from 0.1 to 4.5, respectively. We have observed that the direct allowed gaps have been found to be 1.5 eV and 3 eV for CuPc I; 2.4 eV, 3.2 eV and 3.65 eV for CuPc II. On the other hand, for CuPc III thin films, they have been observed as 1.55 eV, 2.55 eV and 2.9 eV. Differences in optical properties are attributed to different chemical structures of the CuPc molecules in terms of their macrocycle ring size and R-group chain length.

Kinetic and thermodynamic studies of aquation reactions in [RuL2(mac)]q+ complexes: [mac = 1,4,8,11-tetraazacyclotetradecane (cyclam) or 1,4,7,10-tetraazacyclododecane (cyclen); and L = Cl−, OH−, OH2

We report here the synthesis, characterization and kinetic studies of [RuL2(mac)]n+ complexes [mac = 1,4,8,11-tetraazacyclotetradecane (cyclam) or 1,4,7,10-tetraazacyclododecane (cyclen); and L = Cl−, OH−, OH2]. The dichloride complexes release one Cl− producing [RuCl(L)(mac)]n+ or two Cl− producing [Ru(L)2(mac)]n+ (L = OH2, OH−) in aqueous solution within pH 1–7. The product of these reactions were characterized by ultraviolet–visible (UV–Vis) spectroscopy. The chloride affinity of Ru(III) depends on the macrocyclic ring size and geometric structure. The k1 and thermodynamic activation parameters (at pH 4.4, T = 25 °C) of cis-[RuCl2(cyclen)]+ complex are k1 = 3.6 × 10−3 s−1 (25 °C); ΔH# = 40.2 kJ mol−1 and ΔS# = − 138 J K mol−1; under similar conditions, for cis-[RuCl2(cyclam)]+ these values are 2.4 × 10−3 s−1, ΔH# = 50.8 kJ mol−1 and ΔS# = − 119 J K mol−1. The rate of chloride aquation reactions for cis-[RuCl2(cyclen)]+ is about 1.5 times faster than for the cyclam complex. The reactivity difference could be due to a combination of the σ-trans effect, the nephelauxetic effect and the effect of solvation.

Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA).

Teixobactin is a highly potent cyclic depsipeptide which kills a broad range of multi-drug resistant, Gram-positive bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) without detectable resistance. In this work, we describe the design and rapid synthesis of novel teixobactin analogues containing two cysteine moieties, and the corresponding disulfide-bridged cyclic analogues. These analogues differ from previously reported analogues, such as an Arg10-teixobactin, in terms of their macrocyclic ring size, and feature a disulfide bridge instead of an ester linkage. The new teixobactin analogues were screened against Methicillin-resistant Staphylococcus aureus and Methicillin-sensitive Staphylococcus aureus. Interestingly, one teixobactin analogue containing all l-amino acid building blocks showed antibacterial activity against MRSA for the first time. Our data indicates that macrocyclisation of teixobactin analogues with disulfide bridging is important for improved antibacterial activity. In our work, we have demonstrated the unprecedented use of a disulfide bridge in constructing the macrocyclic ring of teixobactin analogues.

A Cyclic Peptide Inhibitor of the iNOS-SPSB Protein-Protein Interaction as a Potential Anti-Infective Agent.

SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design.

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle.

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

The Effect of Modifying the Macrocyclic Ring Size on Zn3Ln (Ln = Dy, Er, and Yb) Single‐Molecule Magnet Behavior

Three tetranuclear heterometallic ZnII‐LnIII complexes of the 30‐membered [3+3] hexaimine macrocycle (LEt)6–, with general formula ZnII3LnIII(LEt)(NO3)2OAc·5H2O (LnIII = DyIII, ErIII, YbIII), were prepared using our established one‐pot synthesis methodology, whereby the individual components of the whole system are poised to assemble themselves into a mixed 3d/f4f macrocyclic system. This uses a 3:1:3:3 reaction of ZnII acetate, the appropriate LnIII nitrate, 1,4‐diformyl‐2,3‐dihydroxybenzene, and 1,2‐diaminoethane. These ten individual building blocks readily assemble into tetrametallic complexes, analogous to our previously reported examples with larger macrocycles. Identity was confirmed by IR spectroscopy (imine), micro‐ (C, H, N) and metal‐ (Zn, Ln) analysis, TGA (solvent content), and mass spectrometry. Magnetic properties were studied down to 2 K and with ac susceptibility measurements were used to check for slow relaxation of the magnetization characteristic of Single‐Molecule Magnet (SMM) behavior. As is often the case for single ion systems (only Ln is paramagnetic) no such behavior was observed. However, under an applied dc field, an out‐of‐phase ac susceptibility signal is seen for all three complexes. We speculate that shrinkage of macrocyclic ring size (30) compared to that of the original ZnII3DyIII system (33) has led to a less favorable coordination arrangement for the DyIII and ErIII ions through a change in the imposed coordination environment of the LnIII ion.

Distribution of benzo-substituted crown-ethers between chloroform and water: effects of macrocycle ring size and lithium chloride

Small size benzo-substituted crown ethers are attractive complexing agents for lithium isotope separation by solvent extraction. Low transfer of the crown ethers from solvent to water is a key point for applicability of the extractants. In the present study, 9- and 12-membered crown ethers were synthesized, and their distribution between chloroform and water was studied. Polyether ring size, benzene substituents and addition of LiCl to water were found to effect on distribution constants. Low losses of the macrocycles were observed at single-stage contact with aqueous phase. However, these losses should be taken into account in the design of multistage processes for the preparation of highly enriched lithium isotopes.

Influence of Macrocyclic Ring Size on the Corrosion Inhibition Efficiency of Dibenzo Crown Ether: A Density Functional Study

The effect of macrocycle ring size on the corrosion inhibition efficiency of dibenzo-12-crown-4 (DB12C4), dibenzo-15-crown-5 (DB15C5), dibenzo-18-crown-6 (DB18C6), dibenzo-21-crown-7 (DB21C7) and dibenzo-24-crown-8 (DB24C8) have been elucidated by mean of density functional calculation at B3LYP/6-31G(d) level of theory in the gas and aqueous environment. The quantum chemical parameters including the frontier orbital energies (EHOMO, ELUMO), ionization potential (I), electron affinity (A), the absolute electronegativity (χ), hardness (η), softness (σ), and the fraction of electron transferred (ΔN) are positively correlated to the corrosion inhibition efficiency (IE%) of the studied crown ethers. The calculation results indicate that DB24C8 exhibits the highest corrosion inhibition efficiency, whereas DB12C4 exhibits the lowest corrosion inhibition efficiency. The results of this study will contribute to design crown ethers potential as corrosion inhibitors.

Synthesis and Characterization of Functionalized [12]Cycloparaphenylenes Containing Four Alternating Biphenyl and Naphthyl Units.

Functionalized [12]cycloparaphenylenes ([12]CPPs) containing four alternating biphenyl and naphthyl units were synthesized. A macrocyclic furan-containing CPP precursor was used for the Diels-Alder reaction with the parent benzyne or 3,6-dimethoxybenzyne to form the corresponding macrocyclic carbon frameworks. The subsequent reductive deoxygenation of the Diels-Alder adducts with Fe2(CO)9 followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone produced the functionalized [12]CPPs. The effect of macrocyclic ring size on the reaction rate of oxidative aromatization was investigated.

ChemInform Abstract: The Versatile Ruthenium(II/III) Tetraazamacrocycle Complexes and Their Nitrosyl Derivatives

AbstractReview: 249 refs.

Crystal structures of two cross-bridged chromium(III) tetra-aza-macrocycles.

The crystal structure of di-chlorido-(4,10-dimethyl-1,4,7,10-tetra-aza-bicyclo-[5.5.2]tetra-deca-ne)chromium(III) hexa-fluorido-phosphate, [CrCl2(C12H26N4)]PF6, (I), has monoclinic symmetry (space group P21/n) at 150 K. The structure of the related di-chlorido-(4,11-dimethyl-1,4,8,11-tetra-aza-bicyclo-[6.6.2]hexa-deca-ne)chromium(III) hexa-fluorido-phosphate, [CrCl2(C14H30N4)]PF6, (II), also displays monoclinic symmetry (space group P21/c) at 150 K. In each case, the Cr(III) ion is hexa-coordinate with two cis chloride ions and two non-adjacent N atoms bound cis equatorially and the other two non-adjacent N atoms bound trans axially in a cis-V conformation of the macrocycle. The extent of the distortion from the preferred octa-hedral coordination geometry of the Cr(III) ion is determined by the parent macrocycle ring size, with the larger cross-bridged cyclam ring in (II) better able to accommodate this preference and the smaller cross-bridged cyclen ring in (I) requiring more distortion away from octa-hedral geometry.